(1) Field of the Invention
The present invention relates to novel cyclopropanoid compositions useful in the synthesis of pyrethroids and to methods of preparing these compositions. The compounds of the invention have the structure ##STR4## where R' is --CH.sub.3 or --CH.sub.2 CH.sub.3 and A is either --H or A, B represents a group having a carbon atom in common with the cyclopropanoid ring, the A, B group having the formula --(CH.sub.2).sub.n -- (n=3, 4, or 5) or --(CH.sub.2).sub.2 --Y--(CH.sub.2).sub.2 -- (Y=NCH.sub.3, O, or S). When A is --H, B is selected from the group consisting of: ##STR5##
In accordance with the method of the present invention, these compounds, as well as other pyrethroid intermediates, can be manufactured from aldehydes in a two step process: ##STR6##
Alicyclic ketones of the formula RR"CO, wherein R,R"=--(CH.sub.2).sub.n --(n=3, 4, or 5) or R,R"=--(CH.sub.2).sub.2 --Y--(CH.sub.2).sub.2 --(Y=NCH.sub.3, O, or S), can also be used as starting materials in lieu of the aldehyde (RCHO).
Although the experimental conditions for a Knoevenagel condensation vary from one starting compound to the next, one can examine the literature for the exact procedure to be followed for a given starting material. An excellent and lengthy review [including a list of various aldehydes and ketones which have been successfully condensed with methyl or ethyl cyanoacetate (listed in Table VII of the review)] can be found in Organic Reactions, 15, pp. 204-599 (1967).
(2) Description of the Prior Art
Because of their low mammalian toxicity, high insecticidal activity, and biodegradability, the pyrethroids have proved quite useful for the control of insect pests. A study of the literature reveals that in the past decade various routes have been developed for the synthesis of these compounds. A collection of a number of methods of preparing certain ester derivatives of trans-chrysanthemic acid and the related synthetic pyrethroids can be found in "Synthetic Pyrethroids", ACS Symposium Series 42, M. Elliott, Ed., American Chemical Society, Washington, D.C., 1977, pp. 45-54, 116-136; and, "The Total Synthesis of Natural Products", Vol. 2, J. ApSimon, Ed., Wiley, New York, 1973, pp. 49-58. A survey of a number of syntheses of pyrethroid acids is reported in Angewandte Chemie, Internat. Ed. Engl., 20, 703-722 (1981).
Of particular interest to the present application are the methods disclosed by Krief et al. and by Annen et al. ##STR7## Reference: A. Krief, DOS 2,615,160 (1976), Roussel-Uclaf; M. J. Devos, L. Hevesi, P. Bayet, and A. Krief, Tetrahedron Lett., 3911 (1976). ##STR8## Reference: K. Annen, et al, Chem. Ber. 111. 3094-3104 (1978).
The Krief et al. process utilizes a phosphorane [(CH.sub.3).sub.2 C.dbd.PPh.sub.3 ] to generate a three-membered ring. Phosphorane reagents are very costly and require one equivalent of a strong base such as n-butyllithium to generate. In addition, phosphoranes must be synthesized in the absence of air and protic solvents (even traces of moisture rapidly destroy them); and therefore this type of process is highly unsuitable for an industrial scale-up. Moreover, the Krief cyclization yields a product which can be used to prepare the acid component of only trans pyrethroids whereas, as illustrated below, the method of the present invention results in either the cis-stereoisomer [which often exhibits greater insecticidal activity--e.g., See: M. Elliott, A. W. Farnum, N. F. Janes, P. H. Needham, and D. A. Pulman, Pesticide Sci., 6, 537 (1975)], or the trans stereoisomer. More significantly, Krief et al. utilized their cyclization with only a few specific compounds, such as those having the structure RCH.dbd.CHCO.sub.2 R'. In sharp contrast, the method of the present invention failed to yield any cyclopropanoids using RCH.dbd.CHCO.sub.2 R' (R=CH.sub.3 or C.sub.6 H.sub.5) and (CH.sub.3).sub.2 CHNO.sub.2 (2-nitropropane) in the presence of base in refluxing alcohol.
Annen et al., utilizes a nitro compound and unsaturated cyanoesters similar to those used in the method of the present invention in order to generate cyclopropanoids. However, these are many significant differences between the Annen et al. procedure and the present method:
Annen's cyclization step, which is preceded by a Michael reaction, utilizes a nitro leaving group bonded to a primary (1.degree.) carbon: ##STR9## The intermediate formed by the Michael reaction in the method of the present invention has the leaving group at a tertiary (3.degree.) center: ##STR10## Due chiefly to steric factors, one would expect the ring closure of this latter structure to be much less favorable (if it proceeds at all) than for the similar process involving Annen's (1.degree.) structure. Any basic textbook in organic chemistry indicates that nucleophilic substitution at a 1.degree. carbon is much faster than at a 3.degree. center. For example, the reaction of CH.sub.3 CH.sub.2 Br with I.sup..theta. is 1,000 times faster than that between (CH.sub.3).sub.3 C--Br and I.sup..theta.. [Reference: Morrison and Boyd, "Organic Chemistry," 3rd Edition, p. 465]. Indeed, the major reaction pathway when nucleophiles interact with 3.degree. halides is often elimination (to yield an alkene) rather than substitution [Reference: Morrison and Boyd, "Organic Chemistry," 3rd Ed., p. 485].
Nothwithstanding these theoretical considerations, the cyclization reaction of the present invention proceeds under considerably milder conditions than those employed by Annen et al. Annen employs metal alcohol at 100.degree. C. (which requires a pressure reactor since the boiling point of CH.sub.3 OH is 65.degree. C.) and excess base accompanied by a very large excess of nitromethane. The method of the present invention procedes readily at 65.degree. C. (refluxing methanol) or 78.degree. C. (refluxing ethanol) and requires only a stoichiometric quantity of base and 2-nitropropane.
Annen et al. shows that his procedure was used successfully to convert ##STR11## in 19% yield. The cyclizatin method of the present invention, using (CH.sub.3).sub.2 CHNO.sub.2, failed when applied to ##STR12## (R'=CH.sub.3 or CH.sub.2 CH.sub.3). The fact that this failure is not simply due to the steric factors involved in forming a fully-substituted ring is illustrated by the fact that a sterically complex cyclopropanoid was formed readily (in less than 5 hours) and in high yield (greater than 70%) using the method of the present invention: ##STR13##
It appears that the process of Annen et al. is most successful when applied to complex steroidal systems and gives poor yields when applied to relatively simple systems. The method disclosed herein, in contrast, proceeds readily in 70-95% yields with a variety of substrates, both simple and complex.